The present invention relates to fluorous tagging or protecting compounds and to methods of use thereof, and especially, to fluorous tagging compounds suitable for use with hydyroxy- and amine-bearing organic compounds.
In traditional organic chemistry, compounds are synthesized as pure substances through well-planned reactions and careful separation. However, in a number of fields, including drug discovery, catalyst design and new material development, tens of thousands of organic compounds must be synthesized and tested to discover a few active ones. In the pharmaceutical industry, for example, synthesizing such a large number of compounds in the traditional way is too slow compared to the rapid emergence of new biological targets. The productivity of orthodox solution (liquid) phase organic synthesis is severely limited by tedious separation processes for the purification of products. Techniques integrating organic reactions with rapid purification/separation procedures are thus highly desirable.
Recently, fluorous synthetic and separation techniques have attracted the interest of organic chemists. In fluorous synthetic techniques, reaction components are typically attached to fluorous groups or tags such as perfluoroalkyl groups to facilitate the separation of products. Organic compounds are readily rendered fluorous by attachment of an appropriately fluorinated phase label or tag. In general, fluorous-tagged molecules partition preferentially into a fluorous phase while non-tagged ones partition into an organic phase.
The fluorous tag preferably fulfills a double role as protective group and phase tag and is removed in the final step(s) of the synthesis. The viability of a fluorous synthesis plan depends greatly on the availability of suitable fluorous protecting groups, but only a few fluorous tags are currently available.
In that regard, the fluorous phase label or tag most often used in fluorous synthesis has been the silane (C10F21CH2CH2)3SiBr 1. In general, the silane is attached to alcohol-bearing substrates using standard conditions to result in a silyl ether, and can be cleaved with fluoride. The silane, however, cannot be recycled. In addition, the powerful electron withdrawing effect of three fluorous chains makes the silyl ether rather labile towards nucleophiles and other polar reactions. Thus, although fluorous synthetic and/or separation techniques are promising, such techniques are currently limited by a lack of availability of suitably versatile fluorous tags.
It is thus very desirable to develop improved fluorous tagging compounds.
For the further development of fluorous phase chemistry into a practical strategy in, for example, combinatorial and parallel synthesis, a variety of fluorous phase labels must be made available. The present invention provides fluorous tags that can be prepared in large quantity, can be installed and removed from a substrate using mild reaction conditions, and can be recyclable after cleavage. In addition, the fluorous tags of the present invention are tolerant, as a group, to a wide range of reaction conditions, such that an appropriate label can be chosen which is amenable to substantially any given sequence of reactions.
The resulting fluorous xe2x80x9ctaggedxe2x80x9d compound can be used in a wide variety of fluorous reaction and/or separation techniques. Several fluorous reaction and separation techniques are disclosed, for example, in U.S. Pat. Nos. 5,859,247 and 5,777,121, the disclosures of which are incorporated herein by reference. The tagging compounds of the present invention are particularly suitable for tagging of compounds bearing hydroxyl groups or nitrogen groups such as amine groups.
As used herein, the term xe2x80x9cfluorousxe2x80x9d, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons or perfluorocarbons, fluorohydrocarbons, fluorinated ethers, fluorinated amines and fluorinated adamantyl groups). For example, perfluorinated ether groups can have the general formula xe2x80x94[(CF2)xO(CF2)y]zCF3, wherein x, y and z are integers. Perfluorinated amine groups can, for example, have the general formula xe2x80x94[(CF2)x(NRa)CF2)y]zCF3, wherein Ra can, for example, be (CF2)nCF3, wherein n is an integer. Fluorous ether groups and fluorous amine groups suitable for use in the present invention need not be perfluorinated, however. The term xe2x80x9cfluorous compound,xe2x80x9d thus refers generally to a compound comprising a portion rich in carbon-fluorine bonds. As used herein, the term xe2x80x9cperfluorocarbonsxe2x80x9d refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms xe2x80x9cfluorohydrocarbonsxe2x80x9d and xe2x80x9chydrofluorocarbonsxe2x80x9d include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. A few examples of suitable fluorous groups Rf for use in the present invention include, but are not limited to, xe2x80x94C4F9, xe2x80x94C6F13, xe2x80x94C8F17, xe2x80x94C10F21, xe2x80x94C(CF3)2C3F7, xe2x80x94C4F8CF (CF3)2, xe2x80x94CF2CF2OCF2CF2OCF3, xe2x80x94CF2CF2 (NCF2CF3) CF2CF2CF3, and fluorous adamantyl groups.
As used herein, the term xe2x80x9ctaggingxe2x80x9d refers generally to attaching a fluorous moiety or group (referred to as a xe2x80x9cfluorous tagging moietyxe2x80x9d or xe2x80x9ctagging groupxe2x80x9d) to a compound to create a xe2x80x9cfluorous tagged compoundxe2x80x9d. Separation of the tagged compounds of the present invention is achieved by using fluorous separation techniques that are based upon differences between/among the fluorous nature of a mixture of compounds. As used herein, the term xe2x80x9cfluorous separation techniquexe2x80x9d refers generally to a method that is used to separate mixtures containing fluorous molecules or organic molecules bearing fluorous domains or tags from each other and/or from non-fluorous compounds based predominantly on differences in the fluorous nature of molecules (for example, size and/or structure of a fluorous molecule or domain or the absence thereof). Fluorous separation techniques include but are not limited chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., xe2x80x9cFluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,xe2x80x9d J. Chromat., 544, 187-199 (1991). Examples of suitable fluorocarbon bonded phases include commercial Fluofix(copyright) and Fluophase(trademark) columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), and FluoroSep(trademark)-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include liquid-liquid based separation methods such as liquid-liquid extraction or countercurrent distribution with a fluorous solvent and an organic solvent.
Preferably, the molecular weight of the fluorous tags of the present invention does not exceed about 2,500. More preferably, the molecular weight does not exceed about 1,750. Even more preferably the molecular weight does not exceed about 1200. Compounds may bear more than one fluorous tag of the present invention.
In one aspect, the present invention provides a method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula: 
wherein Rf is a fluorous group and m is 0, 1 or 2 (that is, the ring can be a five-, six-, or seven-membered ring). The fluorous group can, for example be a fluorohydrocarbon group (for example, fluorous alkyl groups, including fluorous adamantyl groups), a perfluorocarbon group, a fluorinated ether group or a fluorinated amine group. Perfluoroadamantyl group suitable for use in the present invention can, for example, have the following formulas: 
As used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9carylxe2x80x9d and other substituent groups refer generally to both unsubstituted and substituted groups unless specified to the contrary. Unless otherwise specified, alkyl groups are hydrocarbon groups and are preferably C1-C15 (that is, having 1 to 15 carbon atoms) alkyl groups, and more preferably C1-C10 alkyl groups, and can be branched or unbranched, acyclic or cyclic. The term xe2x80x9carylxe2x80x9d refers to phenyl (Ph) or napthyl, substituted or unsubstituted. The term xe2x80x9calkylenexe2x80x9d refers to bivalent forms of alkyl.
The groups set forth above, can be substituted with a wide variety of substituents. For example, alkyl groups may preferably be substituted with a group or groups including, but not limited to aryl groups. Aryl groups may preferably be substituted with a group or groups including, but not limited to, alkyl groups or other aryl groups.
In another aspect, the present invention provides a method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula: 
wherein Rf is a fluorous group as defined above, R1 is a an alkyl group or an aryl group and m is 0, 1 or 2.
A method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula: 
wherein Rf1 and Rf2 are independently, the same or different, fluorous groups, Rs1 is a spacer group, d is 1 or 0 (that is, the spacer group can be present or absent), Rs2 is a spacer group, a is 1 or 0, R2 is a H, an alkyl group or an aryl group, R3 is H or xe2x80x94Rs3eRf3, wherein, Rs3 is a spacer group, e is 1 or 0, and Rf3 is a fluorous group. Numerous types of spacer groups or linkages can be used in the present invention. Examples of spacer groups suitable for use herein include, but are not limited to, alkylene groups (preferably, C1-C6 alkylene groups), 1,2-, 1,3-, or 1,4-divalent phenyl groups or alkoxy alkylene groups (for example, xe2x80x94O(CH2)xxe2x80x94). As used herein, the term xe2x80x9calkylenexe2x80x9d refers generally to a bivalent form of an alkyl group (for example, xe2x80x94(CH2)mxe2x80x94) Alkylene groups may be substituted or unsubstituted.
The present invention also provides a method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula: 
wherein Rf1 and Rf2 are independently, the same or different, fluorous groups, Rs1 is a spacer group, d is 1 or 0 (that is, the spacer group can be present or absent), Rs2 is a spacer group, a is 1 or 0, R4 is an alkyl group or an aryl group, R5 is an alkyl group or an aryl group, R6 is H, an alkyl group, or a fluorinated alkyl group, and X is Cl, Br or I.
In another aspect, the present invention provides a method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula: 
wherein Rf1 is a fluorous group, Rs1 is a spacer group, d is 1 or 0, R4 is an alkyl group or an aryl group, R5 is an alkyl group or an aryl group, and X is Cl, Br or I.
The present invention further provides a compound having the formula: 
The present invention also provides a compound having the formula: 
The present invention also provides a compound having the formula: 
The present invention also provides a compound having the formula: 
The present invention further provides a compound having the formula: 
In another aspect, the present invention provides a method of activating an anomeric sulfoxide to react with an alcohol to form a corresponding ether comprising the step of mixing the anomeric sulfoxide with Cp2ZrCl2, AgClO4, and the alcohol. The anomeric sulfoxide can, for example, have the formula: 
In still another aspect, the present invention provides a method of carrying out a reaction comprising the steps of:
attaching a fluorous tag to a substrate that is bound to a solid support;
cleaving the fluorous-tagged substrate from the solid support while retaining the fluorous tag attached thereto;
reacting the cleaved, fluorous-tagged substrate in a liquid phase reaction to synthesize a fluorous-tagged product; and
separating the fluorous-tagged product from other compounds using a fluorous separation technique.
The method may further include the step of cleaving the fluorous tag from the fluorous tagged product. In one embodiment, the fluorous tag has the formula: 